The Desmond Tutu HIV
Centre, Institute for Infectious Disease and Molecular
Medicine, Faculty of Health Sciences, University of Cape Town

M D Nglazi, MPH

R Kaplan, MD

R Wood, MB BCh, MSc, FCP

L-G Bekker, MB ChB, FCP,
PhD

S D Lawn, MD

International Union
against Tuberculosis and Lung Disease, Paris, France

M D Nglazi, MPH

Department of City
Health, City of Cape Town

J Caldwell, RN, RM, BCur

Provincial Government of
the Western Cape, Cape Town

N Peton, MPA

Department of Infectious
and Tropical Diseases, London School of Hygiene & Tropical
Medicine, London, UK

S D Lawn, MD

Corresponding author: M
Nglazi (Mweete.Nglazi@hiv-research.org.za)

Background. Delivery of integrated care for
patients with HIV-associated TB is challenging. We assessed
the uptake and timing of antiretroviral treatment (ART) among
eligible patients attending a primary care service with
co-located ART and TB clinics.

Methods. In a retrospective cohort study,
all HIV-associated TB patients (≥18 years old) who commenced
TB treatment in 2010 were included. Data were analysed using
basic descriptive statistics and log-binomial regression
analysis.

Results. Of a total of
497 patients diagnosed with HIV-associated TB, 274 were
eligible to start ART for the first time (median CD4 count,
159 cells/µl). ART was started during TB treatment by 220
(80.3%) patients. Among the 54 (19.7%) who did not start ART,
23 (42.6%) were either lost to follow-up (LTFU) or died before
enrolling for ART; 12 (22.2%) were either LTFU or died after
enrolling but before starting ART; 5 (9.3%) were transferred
out; and 14 (25.9%) only started ART after completion of TB
treatment. The median delay between starting TB treatment
and starting ART was 51 days (IQR 29 - 77). Overall, only
58.6% of patients started ART within 8 weeks of TB treatment,
and 12.7% of those with CD4 counts <50 cells/µl started ART
within 2 weeks.

Conclusions. In a setting with co-located TB
and ART clinics, delays to starting ART were substantial, and
one-fifth of eligible patients did not start ART during TB
treatment. Co-location of services alone is insufficient to
permit timely initiation of ART; further measures need to be
implemented to facilitate integrated treatment.

S Afr Med J 2012;102(12):936-939.
DOI:10.7196/SAMJ.6024

South Africa has a high burden of both TB and HIV1,2,3
and a high HIV-associated TB case fatality rate.4
Optimal case management of HIV-associated TB requires
standardised anti-TB treatment combined with
trimethoprim-sulphamethoxazole (co-trimoxazole) prophylaxis
and antiretroviral treatment (ART). ART results in a 64 - 95%
reduction in mortality risk 5 and is an essential
component of care. How soon to start ART after TB treatment
initiation has become clearer from randomised controlled
trials. These show that integration of ART and TB treatment in
all HIV-associated TB patients regardless of CD4 count
significantly improves survival,6 and
that early ART (within 2 weeks of starting TB treatment) was
particularly beneficial for patients with CD4 counts <50
cells/µl.7 These data support the
World Health Organization (WHO) ART 2010 guidelines that
recommend ART is started within 2 - 8 weeks of starting TB
treatment.10

Although the guidelines recommending the optimal time to
start ART in patients with HIV-associated TB have been
established, the delivery of integrated care for these
patients remains challenging. Models of integrated care in
resource-limited countries include: efficient referrals
between separately located TB and ART clinics; provision of TB
and ART services on the same premises but by different service
teams; and fully combined services with provision of TB
treatment and ART from the same staff.11,12
The goal is to provide streamlined care, minimise patient
losses and ensure timely initiation of ART.

Few data exist on patient losses from care and delays in
starting ART among HIV-associated TB patients at different
stages in the cascade between HIV-associated TB diagnosis and
ART initiation in a variety of models of integrated care.13,14,15,16,1718
Delivery of care in South Africa has largely been based within
completely separate TB and ART services. In a primary care
setting in a Cape Town township, we piloted delivery of care
using co-located services in the same facility. We conducted
this retrospective observational cohort study to assess the
uptake and timing of ART initiation and losses from the care
pathway.

Methods

Setting

The study was conducted at Nyanga Community Health Centre
(CHC), Klipfontein health sub-district, Cape Town. An
estimated 420 000 people19 live in this
predominantly low-income urban community, which had an
antenatal HIV-1 prevalence rate of 24% in 2009.20 This
nurse-run, doctor-supported service has provided TB and ART
care for patients since 2008. Here, TB treatment and ART is
delivered by separate health authorities but located in the
same building. Most ART-eligible co-infected patients
receiving TB treatment at the TB clinic were referred to the
ART clinic at the same site, and a minority were
transferred-out to separate ART clinics in different
localities in Cape Town.

The clinic staff at the TB service followed the South
African National TB guidelines21 for TB case detection,
notification and treatment. TB was treated using standardised
rifampicin-based regimens of 6 months’ duration for new TB
cases and 8 months for retreatment cases. During the study
period, the South African ART guidelines were revised: before
April 2010, staff at both TB and ART services followed the
2004 South African ART guidelines which recommended that
patients with CD4 counts of 50 - 200 cells/µl should delay ART
until after 2 months of starting TB treatment, while those
with a CD4 count <50 cells/µl or with serious
co-morbidities should commence ART as soon as possible after
at least 2 weeks of TB treatment.22
After April 2010, the clinic staff were advised to adopt the
2010 South African ART guidelines, which recommended that TB
patients with CD4 cell counts <100 cells/µl or WHO stage IV
should commence ART within 2 weeks of eligibility, and those
with CD4 cell counts ≤350 cells/µl should commence ART within
2 - 8 weeks of starting TB treatment.23

Data sources

The following data sources
were used: (i) Western Cape’s electronic
eKapa TB and ART database which is currently being used at
this clinic. TB data in this database have been prospectively
maintained since October 2009, including demographic and
clinical information on TB patients and on TB treatment visits
and outcomes per TB episode. HIV data have been prospectively
maintained since March 2007, including demographic data and
clinical data on patients’ ART treatment visits and outcomes.
Both HIV and TB episodes are linked to patients using a unique
identifier; (ii) paper-based TB register and
the Western Cape’s electronic TB register (ETR.net) which
monitors TB treatment; (iii) National Health Laboratory
Services (NHLS) database; and (iv) patient records.

Data collection

All HIV-associated TB patients ≥18 years old who were
registered and commenced on TB treatment between January 2010
and December 2010 were included. The Western Cape electronic
data collection system, eKapa was used to obtain information on
demographic characteristics (age and gender), clinical
characteristics (TB disease classification, CD4 count and
patient category) and TB treatment-related variables (date of
starting TB treatment and regimen received). Information was
also obtained on the uptake of ART and the time of ART
initiation during TB treatment. Where information was missing,
it was sought from patient records, NHLS database, paper based
and electronic TB registers. Ethical clearance for the
collection of routine data was obtained from the Research Ethics
Committees of the University of Cape Town and the International
Union against Tuberculosis and Lung Disease.

Definitions

Pre ART losses refer to failure to reach the
next step in the care cascade from starting TB treatment to
starting ART as a result of death and loss to follow-up
(LTFU). Transfer to another TB and ART service was not
regarded as a loss — patients who transfer are assumed to be
retained.

Death refers to all-cause mortality.

Lost to follow-up refers to: (i)
HIV-associated TB patients registered at the TB service who
defaulted TB treatment for ≥8 weeks and failed to enrol in the
ART service; (ii) HIV-associated TB patients who
enrolled in the ART service but failed to attend the ART
service for ≥12 weeks before starting ART; and (iii)
patients classified as LTFU who were not known to have died or
transferred to another facility.

ART eligibility was defined according to the
South African national ART guidelines.22,23

Statistical analyses

Statistical analyses were performed using STATA statistical
software, version 11.0 (STATA Corporation, College Station,
Texas, USA). Basic descriptive statistics were used to
characterise uptake of ART (using proportions) and timing of ART
during TB treatment (using median and interquartile ranges).
Proportions of patients who started ART within specific time
points were calculated and stratified by CD4 count. The CD4
count strata were categorized as <50 cells/µl, and 50 - 200
cells/µl and 200 - 350 cells/µl according to the recent
recommendations and guidelines.7,22,23 The time intervals
considered were ART commencement between 2 and 8 weeks, and we
determined the risk factors associated with starting ART after
more than 8 weeks of TB treatment using log-binomial regression
analysis.

Results

Patient characteristics

A total of 784 patients ≥18 years started TB treatment from
January - December 2010 (Fig. 1). Of these, 10 had unknown HIV
status, 277 were HIV-negative and 497 were HIV-positive. Among
the 497 patients diagnosed with HIV-associated TB, 130 were
already receiving ART at the time of diagnosis (Fig. 1). Of the
367 not yet on ART at the time of TB diagnosis, 363 had CD4 cell
count information available. Because the South African ART
guidelines were revised during the study period, ART eligibility
was assessed using CD4 cell counts <200 cells/µl prior to
April 2010, and CD4 cells counts ≤350 cells/µl after April 2010.
Overall, 274 were ART eligible and therefore formed the patient
cohort of this study that was followed up to determine if ART
was initiated appropriately during TB treatment.

The patient cohort (N=274)
characteristics at the time of start of TB treatment were:
51.8% of HIV-associated TB patients were female and of median
age 34 years (interquartile range (IQR) 29 - 38) (Table 1).
Immunodeficiency was advanced with a median blood CD4
lymphocyte count of 158.5 cells/µl (IQR 69 - 303); 73.4%
co-infected patients had a new diagnosis of TB, and the
majority of 194 (70.8%) were diagnosed as pulmonary TB of whom
50.0% were confirmed smear-negative TB (99/194).

Uptake of antiretroviral treatment

Of the 274 HIV-associated TB patients who were eligible to
start ART for the first time (median CD4 count, 158.5 cells/µl),
ART was started during TB treatment by 220 (80.3%) patients; 54
(19.7%) did not start ART (Fig. 1). Among the patients who did
not start ART, 23 (42.6%) were LTFU or died prior to enrolment
for ART; 12 (22.2%) were LTFU or died after enrolment but prior
to starting ART; 5 (9.3%) were transferred-out; and 14 (25.9%)
only started ART after completion of TB treatment.

Deaths

Among the 54 patients who did not start ART, 15 (27.8%).
patients died; 13 died before enrolment for ART and 2 died after
enrolment but prior to starting ART; 6 (40%) of the 15 patients
who died had CD4 cell counts <50 cells/µl.

Time delays in starting antiretroviral
treatment

Among the 220 known to have started ART
during TB treatment, 215 had ART initiation dates recorded in
patient records. Of these, the overall median time delay between starting TB treatment and
starting ART was was 51 days (IQR 29 - 77). Because of the
survival benefit of starting within 2 weeks of TB treatment in
patients with CD4 counts <50 cells/µl and the national ART
guideline reccommedation to start ART within 8 weeks for those
with CD4 counts <350 cells/µl, we examined delays in
starting ART stratified by CD4 cell count. Among those with
CD4 counts <50 cells/µl, we found that only 12.7% (7/55) of them had started ART within 2
weeks (Table 2). In those with CD4 counts of 50 - 350 cells/µl,
53.1% (85/160) started ART within 8 weeks.

We used univariate and multivariate analyses to determine the
factors associated with starting ART after 8 weeks of TB
treatment. Univariate analyses showed that patients with
reccurrent TB were 2.4 times (95% confidence interval (CI) 1.28
- 4.49) more likey to start ART after 8 weeks of TB treatment
than those with new TB. The risk for starting ART after 8 weeks
of TB treatment was higher among patients with CD4 cell counts
of 50 - 200 cells/µl (risk ratio (RR) 2.29; 95% CI 1.12 - 4.66)
and those with CD4 cell counts of 200 - 350 cells/µl (RR 3.49;
95% CI 1.51 - 8.07) compared with those with CD4 cell counts
<50 cells/µl. Multivariate analyses showed similar results.

Table 1.
Baseline characteristics for TB/HIV co-infected
ART-eligible patients ≥18 years old who started TB
treatment in 2010

Variables

N=274

Age, years

18 - 35

171 (62.4)

≥36

103 (37.6)

Gender

Female

142 (51.8)

Male

132 (48.1)

Patient category

New

201 (73.4)

Retreatment

73 (26.6)

Type of TB*

Smear-negative PTB

99 (36.1)

Smear-positive PTB

95 (34.7)

EPTB

80 (29.2)

CD4 count, cells/µl

<50

68 (24.8)

50 - 200

140 (51.1)

>200

66 (24.1)

TB regimen

Regimen 1

200 (73.0)

Regimen 2

74 (27.0)

PTB = pulmonary TB; EPTB = extra-pulmonary
TB.

*Patients with no smears and having
pulmonary TB were categorised as smear-negative pulmonary TB.
Patients having both pulmonary and extra-pulmonary TB were
categorised as having extra-pulmonary TB.

Table 2.
Duration of delays between starting TB treatment and
starting ART among patients who initiated treatment
with ART start date recorded and stratified by CD4
cell count category

Duration of
delay between starting TB treatment and starting ART

Patients with
CD4

<50 cells/µl (n=55)

Patients with
CD4

50 - 200 cells/µl (n=114)

Patients with
CD4

>200 cells/µl (n=46)

All patients (N=215)

<2 weeks

7 (12.7)

6 (5.3)

2 (4.4)

15 (6.9)

<4 weeks

20 (36.4)

25 (21.9)

8 (17.4)

53 (24.7)

<6 weeks

30 (54.6)

46 (40.4)

11 (23.9)

87 (40.5)

<8 weeks

41 (74.6)

64 (56.1)

21 (45.7)

126 (58.6)

>8 weeks

14 (25.5)

50 (43.9)

25 (54.4)

89 (41.4)

Discussion

In this study, we assessed the proportion of
HIV-associated TB patients who successfully started ART and
the timing of ART initiation during TB treatment. Of eligible
patients, 19.7% (54/274) did not start ART. However, there
were losses in the cascade from ART eligibility to ART
initiation. Of eligible patients who did not start ART, 42.6%
(23/54) were LTFU or died before enrolment for ART, and 22.2%
(12/54) were LTFU or died after enrolment but prior to
starting ART. The delay in starting ART was substantial (51
days) and exceeded the recommendations of the 2010 WHO and
national ART guidelines,10,23 especially for
patients with CD4 cell counts <50 cells/µl. Therefore,
despite co-locating TB and ART services, there are substantial
delays in starting ART during TB treatment, and some patients
did not start ART at all.

Our finding that 20% of eligible patients did not start
ART lies within the range reported elsewhere in sub-Saharan
Africa providing either separate or fully integrated services,
of proportions of 13 - 86%,13,14,16,17 which shows
that there are barriers to successful uptake of ART regardless
of the model of care applied, and further measures must be
implemented to facilitate efficient treatment integration. Of
those not starting ART, 42.6% had died or were LTFU before
enrolment for ART, and 20% of them died or were LTFU after
enrolment but prior to starting ART. These data clearly
indicate that retention in the stage in the cascade from ART
eligibility to ART initiation must be improved. Retention
might be improved by allowing ART services to dispense TB
treatment and vice versa to streamline appointments and reduce
duplication of services. Owing to the retrospective design of
the study, the reasons for the reported losses are unknown.
Possible reasons may include stigma, fear, lack of time to
attend the clinic especially among those who work, and lack of
transport money for additional clinic appointments.16,24
These factors might also have been induced by the presence of
two health authorities rendering either TB or ART services
that were not harmonised owing to organisational differences.
Successful integration of TB and ART services may require
integration at all levels in the health system from clinical
care to community support and administrative structures.

We found an overall median delay in starting ART of 51
days, which is within the range of sub-Saharan Africa
programmes providing either separate or fully integrated TB
and ART services, of median delays between 44 and 110 days.14
While this median falls within the recommended 56 day cut-off,
these patients have advanced HIV and more must be done within
health systems to ensure earlier ART commencement. In
particular, patients most at risk of AIDS mortality (CD4
counts <50 cells/µl) should be fast-tracked for ART; this
may only be achieved if ART is prescribed and administered by
the TB services.

The association between greater delays and higher CD4
cell counts is similar to a study16
among patients accessing separate TB and ART services in Cape
Town, and is in keeping with the clinical recommendation that
severely immunocompromised patients should be prioritised to
initiate ART as soon as possible after starting TB treatment.

The strengths of this study include the tracking of losses at
each stage in the cascade from start of TB treatment to start of
ART, and time delays between starting TB treatment and starting
ART in distinct services in this single primary health clinic.
It provides an understanding of the strengths and limitations of
an alternative model of TB and ART services and the importance
of geographically co-locating these services, although not
necessarily combining the services.

The study limitations are that there is no direct comparison
with alternative models of either geographically separate or
fully combined services; only one clinic with a relatively small
sample size is considered, and the study does not quantify
component delays associated with each step of the cascade from
start of TB treatment to ART initiation. The retrospective
design of the study does not enable us to determine the reasons
for pre-ART losses among co-infected patients. Lastly, the
uptake of ART among ineligible patients is unknown. Future
studies will have to determine what happened to ART-ineligible
patients.

Conclusions

ART services were included on the same premises that provided
TB services at this primary health clinic in the hope of
reducing delays in starting ART and improving ART uptake.
However, this study found delays to starting ART were
substantial, and a fifth of eligible patients did not start ART
at all. These data show that the co-location of services alone
is insufficient to permit timely initiation of ART, and further
measures must be implemented to facilitate integrated treatment.

Acknowledgements. The authors
gratefully acknowledge the dedicated staff of the Nyanga
Community Health Centre. MDN is supported as an operational
research fellow by the International Union Against
Tuberculosis and Lung Disease, Paris, France. SDL is funded by
the Wellcome Trust, London UK. RW is funded in part by the
Cost-Effectiveness of Preventing AIDS Complications (CEPAC)
funded by the National Institutes of Health (NIH, 5
R01AI058736-02), the International Epidemiologic Database to
Evaluate Aids with a grant from the National Institute of
Allergy and Infectious Diseases (NIAID: 5U01AI069924-02),
USAID Right to Care (CA 674 A 00 08 0000 700) and the South
African Centre for Epidemiological Modelling and Analysis
(SACEMA).

12. World Health Organization. WHO
Policy on Collaborative TB/HIV Activities: Guidelines for
National Programmes and other Stakeholders. Geneva: World
Health Organization, 2012.
http://whqlibdoc.who.int/publications/2012/9789241503006_eng.pdf
(accessed 22 May 2012).

12. World Health Organization. WHO
Policy on Collaborative TB/HIV Activities: Guidelines for
National Programmes and other Stakeholders. Geneva: World
Health Organization, 2012.
http://whqlibdoc.who.int/publications/2012/9789241503006_eng.pdf
(accessed 22 May 2012).